The present application claims the priority of Japanese Patent Application No.2000-268885 filed on Sep. 5, 2000, which is incorporated herein.
The present invention relates to a tocotrienol derivative, a process for producing the same and a xcex3-CEHC delivering agent, in particular, an improvement in its bioavailability.
It was revealed that LLU-xcex1 (Loma Linda University-xcex1) is one of natriuretic factors isolated and purified from urine of a uremic patient (Murry E. D. Jr. D., DeWind S. A., Bigornia A. E., D""Amico D. C., King J. G., Pham T., Levine B. H., Jung M. E., Wechter W J., Life Sci. 57, 2145-2161(1995)) and is the same compound as 2,7,8-trimethyl-(xcex2-carboxyethyl)-6-hydroxychromane (xcex3-CEHE: the following formula) which is a xcex3-tocopherol metabolite (Wechter W. J., Kantoci D., Murray E. D. Jr. D""Amico D. C., Jung M. E. Wang W -H., Ptoc. Natl. Acad. Sci USA 93, 6002-6007(1996)). 
This LLU-xcex1 is considered to be a natriuretic factor because it does not affect on a sodium pump of nephron, average arterial pressure and filtration rate of glomerulus, does not inhibit an isozyme of Na+/K+-ATPase and shows the reversible inhibition only on a 70 pS potassium channel of ascending leg of Henle ansa. Therefore, LLU-xcex1 is expected as a diuretic having little side effects on cardiac muscle accompanied by potassium transfer. LLU-xcex1 has an asymmetric carbon at 2-position and there are S-LLU-xcex1 and R-LLU-xcex1. S-LLU-xcex1 has the strongest potassium channel inhibiting activity and S-LLU-xcex1 has a R part at a 2-position and is a main metabolite of d-xcex3-tocopherol.
xcex3-CEHC was revealed to have effects of inhibiting cyclooxygenase-2 (COX-2)(Jiang Q., Elson-Schwab I., Courtemanche C., Ames B. N., Proc. Natl. Acad. Sci. USA97, 11494-11499(2000)) and is expected as an anti-inflammatory agent or an anti-cancer agent having little side effect. In addition, since xcex3-CEHC has the chromanol structure, it can function also as an excellent antioxidant.
On the other hand, it has been revealed that natural type d-xcex3-tocotrienol in which an asymmetric carbon at a 2-position of chroman is R is metabolized effectively into S-xcex3-CEHC in the living body of a rat (Hattori A., Fukushima T., Yoshimura H., Abe K., Imai K., Biol. Pharm Bull.,23, 1395-1397(2000)).
As described above, in order that xcex3-CEHC exerts the functions as a diuretic, an anti-inflammatory agent, an anti-cancer agent or an antioxidant effectively, it is essential to maintain dynamic bioavailability and quantitative bioavailability of xcex3-CEHC. For attaining the maintenance, a method of using xcex3-CEHC itself is contemplated. However, it was revealed that when racemic xcex3-CEHC is administered to a SD rat intravenously, a biological half-life of S-xcex3-CEHC in plasma is 2 minutes or shorter, that of R-xcex3-CEHC is about 1 hour and, in particular, S-xcex3-CEHC having the high activity has a very short half-life (Hattori A., Fukushima T., Hamamura K., Kato M., Imai K., Biomed. Chromatogr., in press). Therefore, it is very difficult to maintain bioavailability of xcex3-CEHC using xcex3-CEHC itself.
On the other hand, since xcex3-tocotrienol and xcex3-tocopherol are metabolized effectively into xcex3-CEHC in the living body, there can be contemplated a method of maintaining bioavailability of xcex3-CEHC by maintaining a level of xcex3-tocotrienol or xcex3-tocopherol in the living body. A method of performing drug delivery of LLU-xcex1 (xcex3-CEHC) using xcex3-tocopherol is described in U.S. Pat. No. 6,048,891. However, both xcex3-tocotrienol and xcex3-tocopherol are unsteable to oxidation and are a compound which is an oily substance having the high viscosity and is not dissolved to water at all, these physicochemical properties make them impossible to be administered by injection. In addition, it is difficult to handle them from a viewpoint of manufacturing pharmacy and there is a problem on storage stability. For these reasons, a method of solubilizing them by adding a large amount of a nonionic surfactant has been studied in order to prepare an aqueous preparation or aqueous cosmetic of tocotrienol. However, a large amount of an surfactant may cause a severe problem such as anaphylaxis shock and the like. In addition, as a tocotrienol derivative having water dispersion or water solubility, tocotrienolsuccinic acid ester and polyethylene glycol derivative of tocotrienolsuccinic acid ester are known (U.S. Pat. No. 5,869,704). However, there is still left a problem that these compounds are oily or waxy at room temperature and reconversion into tocotrienol in the living body is very slow. Therefore, it is difficult to maintain bioavailability of xcex3-tocotrienol and xcex3-tocopherol and, consequently, it is also difficult to maintain bioavailability of xcex3-CEHC.
Like this, the natures normally harbored by tocopherol and tocotrienol have many disadvantageous points in order to enhance their bioavailability.
The first object of the present invention is to provide a tocotrienol derivative which is highly water-soluble and can produce free tocotrienol in the living body.
The second object of the present invention is to provide a xcex3-CEHC delivering agent containing a 6-chromanolcarboxylic acid ester derivative which can produce xcex3-CEHC in the living body.
That is, present tocotrienolcarboxylic acid ester derivative is characterized in that it is represented by the general formula (I): 
(wherein R2 means a carboxylic acid residue having a nitrogen substituent, and R1 and R3 mean a hydrogen atom or a methyl group.)
In addition, in the present invention, it is suitable that the carboxylic acid residue having a nitrogen substituent is at least one selected from the group consisting of residues of amino acid, N-acylamino acid, N-alkylamino acid, N,N-dialkylamino acid, pyridinecarboxylic acid and hydrogen halide salt or alkylsulfonic acid salt thereof.
In addition, a process for producing the tocotrienolcarboxylic acid ester derivative of the present invention comprises protecting a primary or secondary amino group or an amino group of an amino acid having a hydroxy group or a thiol group on a side chain with a protecting group, and subjecting the protecting group-coupled amino acid and tocotrienol to an esterifying reaction.
In addition, the other process for production of the present invention comprises performing an esterifying reaction of a hydrogen halide salt of N,N-dialkylamino acid and tocotrienol in the presence of an active esterifying reagent.
Since a tocotrienol derivative represented by the general formula (I) has an asymmetric carbon at a 2-position of a chromanol skeleton, steric isomers such as d isomer and dl isomer exist The present invention includes these isomers.
In addition, a xcex3-CEHC delivering agent of the present invention includes a water-soluble 6-chromanol derivative represented by the general formula (II) and releases 2,7,8-trimethyl-(xcex2-carboxyethyl)-6-hydroxychromane (xcex3-CEHC) in the living body. (II): 
(wherein R2 means a carboxylic acid residue having a nitrogen substituent.)
In addition, an agent for oral administration of the present invention contains a waterxe2x80x94soluble 6xe2x80x94chromanolcarboxylic acid ester derivative represented by general formula (III): 
(wherein R2 means a carboxylic acid residue having a nitrogen substituent, and R1 and R3 mean a hydrogen atom or a methyl group.) In the above general formulas II and III, R4 is a residue represented by the following formula: 
In addition, a method of improving bioavailability of xcex3-CEHC of the present invention comprises administering the compound of the general formula (II) to the living body.